A Phase 1b/2 Multicenter, International, Randomized, Double Blind, Placebo-Controlled, Study of Gemcitabine Combined With PEGPH20 Compared to Gemcitabine Combined With Placebo in Patients With Stage IV Previously Untreated Pancreatic Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 12
- 主要终点
- Recommended Phase 2 Dose (RP2D)
研究概览
简要总结
Phase 1B: Open label (all patients receive PEGPH20+gemcitabine), dose escalation, safety and tolerability study to determine the safe dose of PEGPH20 to use in combination with gemcitabine in Stage IV previously untreated pancreatic cancer patients.
Phase 2: Randomized, double blind study to compare the effect of overall survival of gemcitabine plus PEGPH20 vs gemcitabine plus placebo in Stage IV previously untreated pancreatic cancer patients.
详细描述
PEGPH20 is a PEGylated version of human recombinant PH20 hyaluronidase that, in preclinical studies, has been shown to remove HA from the extracellular matrix surrounding tumor cells by depolymerizing this substrate. 87% of pancreatic ductal adenocarcinomas (PDA) overexpress HA. PDA tumor tissue may be especially sensitive to the HA-degradation properties of PEGPH20 and thus more responsive to the cytotoxic effects of a given dose of gemcitabine. Modifying the extracellular environment to increase the penetration and efficacy of anti-cancer agents represents a novel approach to treating pancreatic cancer and may provide important therapeutic outcomes in patients with Stage IV Previously Untreated Pancreatic Cancer.
This Phase 1B/2 study will assess safety, tolerability, treatment effect, and various PK/PD endpoints.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with histologically confirmed Stage IV adenocarcinoma of the pancrease previously untreated for metastatic disease
- •One or more metastatic tumors measurable on CT scan per RECIST 1.1 criteria
- •Life expectancy of at least 3 months
- •Signed, written IRB/EC-approved informed consent
- •A negative serum pregnancy test, if female
排除标准
- •Known brain metastasis
- •New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 12 months
- •Active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy
- •Known allergy to hyaluronidase
- •Women currently pregnant or breast feeding
研究组 & 干预措施
Gemcitabine
Gemcitabine + Placebo
干预措施: Gemcitabine (Drug)
Gemcitabine
Gemcitabine + Placebo
干预措施: Placebo (Drug)
PEGPH20
PEGPH20+Gemcitabine
干预措施: Gemcitabine (Drug)
PEGPH20
PEGPH20+Gemcitabine
干预措施: PEGPH20 (Drug)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D)
时间窗: first 4 weeks of Cycle 1
The safety and tolerability profile of PEGPH20 used in combination with gemcitabine was assessed by determining the RP2D, the highest dose level at which no more than 1 of 6 evaluable participants experienced a DLT in the first 4 weeks of treatment (considered a safe dose). The RP2D was determined based on review of safety and pharmacokinetic (PK) data from participants enrolled during the dose-escalation phase of the study.
Number of Participants With a Dose-limiting Toxicity (DLT)
时间窗: first 4 weeks of Cycle 1
The safety and tolerability profile of PEGPH20 used in combination with gemcitabine was assessed by measuring the number of participants with a DLT during the dose-escalation phase of the study. A DLT was defined as any treatment-emergent National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE), Version 4.0, Grade 3 or greater event occurring within the first 4 weeks of treatment that was considered related to PEGPH20. Any PEGPH20 treatment-related AE that resulted in a drug interruption or reduction might have been considered a DLT at the Investigator's or Sponsor's discretion. Hypersensitivity/infusion reactions related to PEGPH20 dosing were not considered DLTs.
次要结局
- Observed Maximum Plasma Concentration (Cmax) Following Single PEGPH20 Doses(Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- Cmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks(Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- Time to Reach Cmax (Tmax) Following Single PEGPH20 Doses(Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites(Baseline; 24 hours hours; end of Cycle 1 (Week 7))
- Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites(Baseline; 24 hours hours; end of Cycle 1 (Week 7))
- Last Measurable Observed Plasma Concentration (Cmin) Following Single PEGPH20 Doses(Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- Cmin Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks(Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- Tmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks(Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- Apparent Half-life (t1/2) Following Single PEGPH20 Doses(Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- t1/2 Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks(Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Measurable Plasma Concentration (AUC0-T) Following Single PEGPH20 Doses(Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- AUC0-T Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks(Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given))
- Plasma Hyaluronan (HA) Concentration at Baseline and After PEGPH20 Administration(Baseline; post-Baseline (average treatment duration of 94.6 days))
- Progression-free Survival (PFS)(from the first dose of PEGH20 until objective tumor progression or death (up to approximately 2 years 4 months))
- Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml(up to the end of Cycle 10 (up to Week 44))
- H-scores, as an Assessment of HA Staining Changes in Tumor Biopsies(Screening; Cycle 1 Week 7)
- Percent Change in in the Maximum Standardized Uptake Value (SUVmax), as an Assessment of Total Lesion Metabolic Activity(Baseline; up to 32 weeks for each individual participant (end of Cycle 7))
- Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1(up to approximately 2 years 4 months)
- Objective Response Rate(up to approximately 2 years 4 months)
- Disease Control Rate(up to approximately 2 years 4 months)
- Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders(up to the end of Cycle 10 (up to Week 44))
- Overall Survival(from the time of the first dose of PEGPH20 until death (up to approximately 2 years 4 months))
- Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9)(up to the end of Cycle 10 (up to Week 44))